Beyond cDC1: Emerging Roles of DC Crosstalk in Cancer Immunity

Dendritic cells (DCs) efficiently process and present antigens to T cells, and by integrating environmental signals, link innate and adaptive immunity. DCs also control the balance between tolerance and immunity, and are required for T-cell mediated anti-tumor immunity. One subset of classical DCs, cDC1, are particularly important for eliciting CD8 T cells that can kill tumor cells. cDC1s are superior in antigen cross-presentation, a process of presenting exogenous antigens on MHC class I to activate CD8+ T cells. Tumor-associated cDC1s can transport tumor antigen to the draining lymph node and cross-present tumor antigens, resulting in priming and activation of cytotoxic T cells. Although cross-presenting cDC1s are critical for eliciting anti-tumor T cell responses, the role and importance of other DC subsets in anti-tumor immunity is not as well-characterized. Recent literature in other contexts suggests that critical crosstalk between DC subsets can significantly alter biological outcomes, and these DC interactions likely also contribute significantly to tumor-specific immune responses. Therefore, antigen presentation by cDC1s may be necessary but not sufficient for maximal immune responses against cancer. Here, we discuss recent advances in the understanding of DC subset interactions to maximize anti-tumor immunity, and propose that such interactions should be considered for the development of better DC-targeted immunotherapies

The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells

Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4+ T cells upon T cell receptor stimulation. IL-21 production by CD4+ T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4+ T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity

IFN-gamma production by CD4 T cells requires Histamine H1 receptor during their initial phase of activation (87.25)

Abstract Histamine H1 receptor (H1R) signaling in T cells plays an important role Th1 effector functions. H1R is an autoimmune susceptibility gene controlling experimental autoimmune encephalomyelitis (EAE). H1R knockout (H1RKO) mice also develop significantly less severe EAE compared to C57BL/6J wild-type mice in association with immune deviation of the CD4+ T-cell response from a Th1- to a Th2-like response. Little is known about the role of direct H1R signaling in the regulation of T-cell effector responses. In this study, T-cells from C57BL/6J and H1RKO mice were used to study H1R signaling in directly regulating such responses. Attempts to restore IFN-gamma&amp;#61472;production in H1RKO T-cells following retroviral transduction of the H1R were unsuccessful. In contrast, H1RKO transgenic mice selectively expressing the H1R in peripheral CD4+ T-cells under the control of the distal-lck promoter restored the IFN-gamma response and susceptibility to EAE in an H1R gene dose-dependent fashion. Moreover, activated H1RKO CD4+ T-cells show reduced phosphorylation of p38 MAP kinase compared to T-cells from wild-type mice which was again restored in activated T-cells from transgenic mice. These results show that H1R signaling regulates IFN-gamma production in CD4+ effector T-cells by direct signaling during initial activation of naïve T-cells through phosphorylation of p38 MAP kinase.</jats:p

The role of the activating versus inhibitory classes of G protein coupled histamine receptors on experimental allergic encephalomyelitis susceptibility. (47.2)

Abstract Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) augmented by histamine (HA) and histamine receptor (HR) signaling. To help elucidate the mechanism behind HA and HR signaling on MS susceptibility, we utilize the experimental allergic encephalomyelitis (EAE) mouse model for MS and implement the use of traditional gene knockout studies. HA is known to exert its effects through four different G protein coupled receptors (GPCRs) designated as H1R, H2R, H3R and H4R. H1R and H2R couples to the Gαq/11 and Gs class of activating G proteins, respectively, whereas H3R and H4R couples to the Gi/o class of inhibitory G proteins. Each individual HR has been shown to influence EAE pathogenesis. Here we assessed the overall contribution to EAE susceptibility imposed by the two classes of GPCRs by generating C57BL6/J mice deficient for both H1R and H2R (H1H2RKO), as well as mice deficient for both H3R and H4R (H3H4RKO). The results of our study show that H1H2RKO mice exhibit decreased susceptibility to EAE, less severe neuroinflammation with a higher infiltration of T regulatory cells into the CNS, and decreased blood brain barrier permeability compared to H3H4RKO mice. Moreover, we show that splenocytes from immunized H1H2RKO mice produce significantly less IFN-γ and IL-17, which are cytokines known to exacerbate disease. Therefore, the activating class of GPCRs enhances EAE susceptibility compared to the inhibitory class of HRs.</jats:p

TGF-β-dependent suppression of IL-22 production in TH17 cells is mediated by the transcription factor c-Maf (163.2)

Abstract T helper (TH) cells modulate immune responses to better cope with various types of invading pathogens through the production of different effector cytokines. TH17 cells produce Interleukin(IL)-17, and IL-22, and play an indispensable role in host defense against infections of extracellular pathogens. IL-22, a member of the IL-10 cytokine family, enhances proinflammatory innate defense mechanisms from epithelial cells, and provides crucial tissue protection from damages caused by inflammation and infection. Transforming growth factor (TGF)-β differentially regulates IL-22 and IL-17 expression. IL-6 alone promotes T cells to only produce IL-22, whereas the combination of IL-6 with high concentrations of TGF-β results in production of IL-17 but not IL-22. Here we identify the transcription factor c-Maf, which is induced by TGF-β, as a downstream repressor of Il22. c-Maf binds to the Il22 promoter, and is both necessary and sufficient for the TGF-β-dependent suppression of IL-22 production in TH17 cells. While a number of factors, such as RORγt, AhR and BATF, have been identified as positive regulators of IL-22 expression, c-Maf is the first transcription factor shown to be involved in its negative regulation. This is even more surprising since c-Maf at the same time is critical in promoting the expression IL-10 and IL-21 in T cells.</jats:p

H1R signaling in antigen presenting cells is dispensable for eliciting pathogenic T cells in experimental allergic encephalomyelitis (123.14)

Abstract The histamine H1 receptor (Hrh1/H1R) was identified as a shared autoimmune disease (SAID) gene in experimental allergic encephalomyelitis (EAE) and autoimmune orchitis, the principal AI models of multiple sclerosis (MS) and idiopathic male infertility, respectively. As a SAID gene, Hrh1/H1R can exert effects in multiple cell types including endothelial cells, T cells, and antigen presenting cells at critical check points during both the induction and effector phases of disease. In this regard, we showed that selective re-expression of H1R by endothelial cells in Hrh1-KO (H1RKO) mice significantly reduced disease severity whereas H1R expression by H1RKO T cells complemented EAE severity and cytokine responses. Given that the H1R has been reported to influence innate immune cell maturation, differentiation, chemotaxis, and cytokine production, which in turn influences CD4+ T cell effector responses, we selectively re-expressed H1R in CD11b+ myeloid cells of H1RKO mice to test the hypothesis that H1R signaling in these cells contributes to EAE susceptibility and/or T cell effector responses. We demonstrate that transgenic re-expression of H1R by H1RKO-CD11b+ cells neither complements EAE susceptibility nor T cell cytokine responses. These results further highlight the cell-specific effects that an AID gene can play in the pathogenesis of complex diseases such as EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.</jats:p

Evidence supporting the existence of a novel histaminergic pathway in the regulation of EAE susceptibility (143.51)

Abstract Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune disease model of multiple sclerosis (MS). Histidine decarboxylase deficient mice (HDCKO), which are unable to synthesize HA, exhibit more severe EAE and increased IFN-γ production by splenocytes in response to MOG35-55. HA exerts its effects through four different G protein coupled receptors (GPCR): H1, H2, H3 and H4 (H1-4R). Each HA-receptor has been shown to influence EAE pathogenesis. In the mammalian brain there is, however, evidence for the existence of non-GPCR signaling by HA which is picrotoxin-sensitive and mediated by chloride conductance. GABAA receptor subunits can form HA-gated chloride channels in vitro suggesting that an ionotropic HA-receptor might contain known ligand-gated chloride channel subunits. To test the hypothesis that non-GPCR signaling by HA plays a role in immune responses, we generated H1-4RKO mice and studied their susceptibility to EAE. Here we report that in contrast to HDCKO mice, H1-4RKO mice develop less severe EAE compared to WT animals. Furthermore, splenocytes from immunized H1-4RKO mice produce significantly less IFN-γ compared to WT mice. Taken together these data support the existence of a novel HA signaling pathway in regulating EAE susceptibility.</jats:p

Combinatorial roles for histamine H1-H2 and H3-H4 receptors in autoimmune inflammatory disease of the central nervous system

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H(1)–H(4). We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H(1)R and H(2)R are propathogenic, while H(3)R and H(4)R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H(1)H(2)RKO and H(3)H(4)RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H(1)H(2)RKO mice developed a less severe clinical disease course, whereas the disease course of H(3)H(4)RKO mice was more severe. H(1)H(2)RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H(3)H(4)RKO mice. Additionally, splenocytes from immunized H(1)H(2)RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases